With an increase of people who lead a life with excess energy intake that is more than the amount necessary for vital activities and that is due to factors, such as intake of high-calorie meals and beverages, a reduced amount of daily exercise, and reduced basal metabolism associated with muscle weakness, the number of young people as well as middle-aged and elderly people who develop diabetes or exhibit insulin resistance is increasing. The aging of fat cells is also known to cause insulin resistance. Elderly people with reduced basal metabolism and a reduced exercise amount also have a high risk of developing diabetes.
In this way, changes in everyday life and a shift towards older societies tend to lead to an explosive increase in diabetic patients every year, and the number of people with abnormal blood sugar metabolism, who are people with pre-diabetes, is also considered to be several times larger than the number of diabetic patients. In fact, similar trends are also apparent from the National Health and Nutrition Examination Survey and Diabetes Survey. An increased diabetic population in Japan is considered to be a serious problem. Under these circumstances, efforts “not to exacerbate an existing pathological condition in diabetic patients” and “not to develop diabetes in insulin-resistant people” are important, because diabetes is a disease that cannot be fundamentally cured.
As such efforts, there are “methods for preventing the onset of diabetes or treating diabetes by controlling the blood sugar level within a normal range.” Specifically, there are methods such as diet therapy, exercise therapy, and pharmacotherapy. Methods using one or a combination of these therapies are actually performed according to the circumstances and condition of the target patient. However, it is often difficult to continue diet therapy that restricts calorie intake or exercise therapy that requires performing exercise for a certain period of time or longer. In particular, there are more and more cases in which it is difficult, with the above therapies alone, to treat elderly people who not only have reduced basal metabolism, but also a significantly reduced amount of exercise with significantly reduced exercise capacity. On the other hand, pharmacotherapy also cannot be a satisfactory combating method from the viewpoint of preventing healthcare cost increase, and is difficult to be used as a method for preventing the onset of diabetes.
Accordingly, with a focus on sugar metabolism in skeletal muscle that severely affects blood sugar metabolism, attempts have been made to develop means for dramatically enhancing diabetes onset-preventing effects and diabetes pathology-improving effects by being used alone or together with conventional therapeutic or preventive methods.
One of the physiological functions that lower blood sugar level is a “metabolism function through uptake of blood sugar from blood vessels (blood) into skeletal muscle.” The following action is known as a mechanism of this function: “skeletal muscle contraction stimulates phosphorylation (activation) of intracellular AMP kinase, which causes translocation of glucose transporter 4 in the cytoplasm into the cell membrane, thus resulting in blood sugar uptake into skeletal muscle cells.” It has also been revealed that that sugar uptake into skeletal muscle cells does not necessarily require skeletal muscle contraction, but is caused by activation of AMP kinase. Accordingly, even when exercise cannot contract skeletal muscle, the function of blood sugar uptake into skeletal muscle is potentially achievable just like exercise is performed. In recent years, while focusing on this point, several “attempts to reduce blood sugar concentration by oral intake of a substance that activates AMP kinase” have been proposed (Patent Literature (PTL) 1 and Patent Literature (PTL) 2).
Further, the following action is also known as another mechanism of sugar uptake from blood vessels (blood) into skeletal muscle cells: “blood insulin binds to an insulin receptor on a cell membrane surface via skeletal muscle interstitial stroma and activation of signaling molecules, such as activation by Akt phosphorylation, causes translocation of glucose transporter 4 in the cytoplasm into the cell membrane, thus resulting in blood sugar uptake into skeletal muscle cells.” In this mechanism, the pathway through which insulin is transported from capillary vessels supplying skeletal muscles to skeletal muscle interstitial stroma also plays an important role. It is known that an increase in capillary surface area and blood flow resulting from an increase in diastolic function through e-NOS activation etc. in skeletal muscle capillaries or an increase in capillary density by angiogenesis enhances the transport of insulin into cells, thus improving sugar metabolism (Non-patent Literature 1 (NPL) 1).
The former AMP kinase-mediated mechanism and the latter insulin-mediated mechanism function independently from each other, and both can be expected to exhibit high sugar uptake effects. While these two mechanisms are normally expressed in healthy persons, the latter mechanism is reduced or lost in diabetes patients or insulin-resistant persons. Accordingly, expressing these two mechanisms in concert, or enhancing these two mechanisms, might potentially achieve a condition more similar to that of healthy persons. However, there is no known method that enables both of the mechanisms to be expressed, and a proposal for a specific method for the solution has been desired.